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Potentials of cancer gene therapy

Genes define all aspects of our life and determine all characteristic that we posses: color of our eyes, height, favorite food and music and susceptibility to various disorders. With over 200 different cancer types and increasing number of sick people all over the globe - cancer is the plague of 21st century. A lot of treatments were discovered so far, but we still don't have perfect tool against cancer. Gene therapy appeared recently and already showed promising effects in the treatment of malignant disorders, but a lot of work still had to be done before we can be sure that mankind won a battle against the cancer.

Early recognition is usually the best chance for patients to survive the cancer. Unfortunately, some types can’t be recognized until disease is in advanced stage, when nothing can be done. Ovarian cancer is typical example of a cancer that doesn’t show any clinical manifestation in the early stage of disease, and when it is diagnosed - effective therapeutic solution doesn't exist. Extensive research in this area identified gene responsible for ovarian cancer. Experiments focused on gene silencing showed that this technique can be perfect solution in treatment of ovarian cancer.

HMGA2 protein belongs to the high mobility group of nuclear nonhistone phosphoproteins. Since HMGA2 is one of chromosomal proteins, it is included in chromatin organization, control of the cell cycle, interaction with transcriptional factors and cellular senescence. HMGAs gene is active during embryonic development. Completed cell differentiation is signal for gene regulators to silence HMGA2. Expression of this gene in adults is associated with myeloproliferative disorder, retinoblastoma, breast, ovarian and non-small lung cancer. Most probably, malfunction of regulatory factors, which keep HMGA2 silenced, result in activation of the gene expression. This gene is not associated with any cellular function in adult, differentiated cell, and thus it is ideal candidate for gene silencing. Series of experiments using ovarian cancer cell lines showed that gene silencing result in cell growth arrest, by keeping the cells in the G1 phase (which precedes mitosis). Experiments continued in vivo on mice. Injection of antisense HMGA2 fragments showed excellent results. All animals survived the treatment and HNGA2 silencing resulted in shrinkage or even disappearance of the cancer tissue (depending on a dose and duration of the treatment). Ideal gene candidate for gene silencing must not be implicated in important cellular processes because silencing would disturb not just cancer proliferation but some other vital process that would be equally harmful for the healthy tissue. This experiment and identified gene represent an example of ideal gene candidate for cancer therapy. After final evaluation in lab animals, it can become part of regular ovarian cancer treatments in humans.

Genetic profile of cancer patients can be useful predictor of effectiveness in a standard drug treatment. International Genome Consortium is alliance of laboratories that collect list of mutations associated with various cancer types. This base already contains genetic profiles of 3000 breast cancers samples (among others cancer types); main goal is to improve treatment options by choosing the most effective therapy. Different drugs are used in cancer treatment, but patients show unequal response even though they have the same disease. Group of women with estrogen receptor positive breast cancer were genotyped and list of mutated genes were identified. Healthy women served as “control”, to help distinguish modified from normal genes. Mutations in genes p53 (cancer suppressor), MAP3K1 and MAP2K4 (cell growth promoters) were expected, but five genes associated with leukemia came as a surprise. When clinical data was compared with altered genes, it was shown that women with mutated p53 genes don’t respond equally well as women that have normal version of the gene. Also, women with mutation in MAP3K1 and MAP2K4 showed better response to the currently applied drug than women that carry normal version of these genes. This experiment showed that genotyping (that is not as expensive as it was before), can be useful tool prior choosing appropriate cancer therapy.

Gene therapy has massive potential and numerous applications in medicine. Cancer could be treated through gene silencing or by choosing ideal (most effective) drug treatment. Common factor in both methods is selection of ideal gene candidate. That is usually the hardest part in gene targeted cancer therapy.